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Objective <p>Emerging evidence links the plasma lipidome to venous thromboembolism, but its causal relationship with portal vein thrombosis (PVT) remains unexplored. This study aimed to systematically screen for potential causal associations between 179 plasma lipid species and PVT risk, aiming to identify candidate biomarkers and explore underlying biological pathways.</p> Methods <p>Using publicly available genome-wide association study (GWAS) data, we performed a two-sample Mendelian randomization (MR) analysis to assess the causal relationships between 179 plasma lipid species and PVT. Inverse-variance weighted (IVW) was the primary method, heterogeneity and pleiotropy were applied to evaluate potential pleiotropy and heterogeneity, and leave-one-out analysis verified result reliability. For lipid species showing nominally significant associations with PVT, lead SNPs were mapped to candidate genes to explore potential biological mechanisms.</p> Results <p>IVW analysis identified nominally significant associations (<i>p</i> &lt; 0.05) between 19 lipid species and PVT risk. 11 lipids showed positive associations (OR = 1.517–1.917), predominantly phosphatidylcholine and sterol ester subtypes. Eight lipid species showed inverse associations (OR = 0.479–0.677), predominantly triacylglycerol and phosphatidylinositol subtypes. Sensitivity analyses supported the robustness of these nominal associations, with no evidence of significant heterogeneity or horizontal pleiotropy. Leave-one-out analysis further confirmed the stability of the estimates. However, after multiple testing correction, none of the associations remained statistically significant (all q &gt; 0.05). These nominally associated lipid species were linked through their lead SNPs to key lipid metabolism genes (FADS1, FADS2, APOE, APOA5, LIPC), which have established roles in pathways relevant to thrombosis.</p> Conclusion <p>Our study suggests potential links between specific plasma lipid species and PVT, although these associations did not survive rigorous multiple testing correction. It provides preliminary evidence that certain lipid species, notably phosphatidylcholine and sterol esters, may be implicated in PVT risk. The mapping of these lipids to candidate genes involved in lipid metabolism (FADS1, FADS2, APOE, APOA5, LIPC) offers mechanistic hypotheses for future research. Further studies are required to validate these preliminary associations and assess their translational potential.</p>

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Mendelian randomization identifies causal effects of phospholipids on portal vein thrombosis risk: FADS1/2-mediated pathways and their potential as diagnostic biomarkers

  • 期刊论文

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  • 发表日期：

    2026年1月17日

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  • Yuwei Wang

摘要

Objective

Emerging evidence links the plasma lipidome to venous thromboembolism, but its causal relationship with portal vein thrombosis (PVT) remains unexplored. This study aimed to systematically screen for potential causal associations between 179 plasma lipid species and PVT risk, aiming to identify candidate biomarkers and explore underlying biological pathways.

Methods

Using publicly available genome-wide association study (GWAS) data, we performed a two-sample Mendelian randomization (MR) analysis to assess the causal relationships between 179 plasma lipid species and PVT. Inverse-variance weighted (IVW) was the primary method, heterogeneity and pleiotropy were applied to evaluate potential pleiotropy and heterogeneity, and leave-one-out analysis verified result reliability. For lipid species showing nominally significant associations with PVT, lead SNPs were mapped to candidate genes to explore potential biological mechanisms.

Results

IVW analysis identified nominally significant associations (p < 0.05) between 19 lipid species and PVT risk. 11 lipids showed positive associations (OR = 1.517–1.917), predominantly phosphatidylcholine and sterol ester subtypes. Eight lipid species showed inverse associations (OR = 0.479–0.677), predominantly triacylglycerol and phosphatidylinositol subtypes. Sensitivity analyses supported the robustness of these nominal associations, with no evidence of significant heterogeneity or horizontal pleiotropy. Leave-one-out analysis further confirmed the stability of the estimates. However, after multiple testing correction, none of the associations remained statistically significant (all q > 0.05). These nominally associated lipid species were linked through their lead SNPs to key lipid metabolism genes (FADS1, FADS2, APOE, APOA5, LIPC), which have established roles in pathways relevant to thrombosis.

Conclusion

Our study suggests potential links between specific plasma lipid species and PVT, although these associations did not survive rigorous multiple testing correction. It provides preliminary evidence that certain lipid species, notably phosphatidylcholine and sterol esters, may be implicated in PVT risk. The mapping of these lipids to candidate genes involved in lipid metabolism (FADS1, FADS2, APOE, APOA5, LIPC) offers mechanistic hypotheses for future research. Further studies are required to validate these preliminary associations and assess their translational potential.